Viral and Genetic Regulation of Abnormal OCL Activity in PD

PD 中异常 OCL 活性的病毒和遗传调控

基本信息

批准号：
8315745
负责人：
DEBORAH Lynn GALSON
金额：
$ 31.54万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-16 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8315745
关键词：
Animal Model CCAAT-Enhancer-Binding Proteins CREB1 gene Calcineurin Cells Complex Cytokine Signaling Funding Genes Genetic Transcription Grant IKKepsilon IRF3 gene Interleukin-6 Link MAP Kinase Gene MAPK14 gene Measles virus nucleoprotein Mediating Messenger RNA Molecular Mutation NF-kappa B Osteoclasts Paget&apos s Disease Pathogenesis Pathway interactions Phenotype Phosphorylation Phosphotransferases Proteins Regulation Reporting Research Personnel Role Scaffolding Protein Serine Signal Transduction TANK-binding kinase 1 TNF gene TNFSF11 gene TRAF2 gene Transcription Factor AP-1 Tumor Necrosis Factor-alpha Up-Regulation Vitamin D3 Receptor activating transcription factor cofactor cytokine factor C human TNF protein in vivo insight novel osteoclastogenesis p65 programs protein expression response transcription factor virus genetics

项目摘要

Both viral and genetic factors have been implicated in the pathogenesis of Paget's disease (PD). However, the molecular mechanisms responsible for their effect on osteoclast (OCL) formation and activity in PD are unclear. It is our hypothesis that measles virus nucleoprotein (MVNP) mediates its effects in OCL precursors predominantly through increased NFicB signaling via activation of the two kB kinase (IKK)-related kinases IKKe (also called IKK-/) and TANK-binding kinase 1 (TBK1) and increased levels of RIP1 and TRAF2. This results in upregulation of IL-6 and a vitamin D receptor coactivator TAFM-17 and increases OCL formation. MVNP also drives multi-potential cells towards the OCL lineage through increased expression and activation of NFATd. The p62P392L mutation linked to PD enhances the effects of MVNP by further increasing NFxB signaling in response to TNF-ct and RANKL as well as increasing p38 MAPK activation in response to RANKL, TNF-alpha and 1,25-(OH)2D3. In support of this hypothesis, we recently found that MVNP expression increases RIP1, TRAF2, and p65 NFicB resulting in enhanced constitutive activation of NFicB, and increased NFicB responsivity to TNF-alpha and RANKL. We also found that MVNP increases NFATd and synergistically activates NFATcl-driven gene transcription, with either NFATd 'or RANKL, and induces IL-6 and TAFn-17. In addition, the p62p392L mutation activates NFicB and increases the sensitivity of OCL precursors to RANKL and TNF-alpha. MVNP also interacts with IKKe and TBK1 to activate NFKB but their role in PD are unknown. In this project we will: 1. Determine if MVNP activation of NFKB and induction of pagetic OCL formation results from alterations of the canonical pathway and/or utilization of an alternative pathway that involves activation of IKKepsilon/TBK1 and the effects of co-expression of MVNP and p62P392L on these pathways. 2. Determine if NFKB activation by MVNP is sufficient for induction of IL-6 or if other mechanisms are also necessary, and the effects of co-expression of p62R392L and MVNP on the molecular mechanlsm(s) identified above. 3. Determine if the synergy of MVNP with NFATd is due to modulation of NFATd activation or of a cofactor of NFATd. The studies of the molecular mechanisms responsible for MVNP and p62p392L effects on OCL formation outlined above" will provide important insight into the pathogenesis of PD and are directly linked to the cellular and in vivo studies proposed in Project 2,

病毒和遗传因素都与paget病（PD）的发病机理有关。但是，尚不清楚其对破骨细胞（OCL）形成和活性的影响的分子机制尚不清楚。我们的假设是，通过激活两个KB激酶（IKK）相关激酶IKKE IKKE（也称为IKK-/）和储罐结合激酶1（TBK1）和TBK1和TRAFFAFF22，是通过激活NFICB信号通过增加NFICB信号传导，主要通过增加NFICB信号传导来介导其在OCL前体中的影响。这会导致IL-6和维生素D受体共激活剂TAFM-17的上调，并增加了OCL的形成。 MVNP还通过增加表达和激活NFATD将多电位细胞驱动到OCL谱系。与PD相关的P62P392L突变通过进一步增加NFXB信号转导对TNF-CT和RANKL的响应，并增加了P38 MAPK激活，从而增强了MVNP的影响，并增加了P38 MAPK激活，以响应RANKL，TNF-ALPHA和1,25-（OH）2d3。为了支持这一假设，我们最近发现MVNP表达增加了RIP1，TRAF2和P65 NFICB，从而增强了NFICB的组成型激活，并提高了NFICB对TNF-Alpha和RankL的反应性。我们还发现，MVNP增加了NFATD并协同激活NFATCL驱动的基因转录，NFATD'或rankl'或rankL诱导IL-6和TAFN-17。此外，p62p392l突变激活了NFICB，并增加了OCL前体对RANKL和TNF-ALPHA的敏感性。 MVNP还与Ikke和TBK1相互作用以激活NFKB，但它们在PD中的作用尚不清楚。在此项目中，我们将：1。确定NFKB的MVNP激活以及Pagetic OCL形成的诱导是否是由于规范途径的改变和/或使用涉及Ikkepsilon/tbk1激活的替代途径的改变以及/或使用MVNP和p62p392l的共表达影响。 2。确定MVNP的NFKB激活是否足以诱导IL-6或是否还需要其他机制，以及是否需要p62r392L和MVNP对上述分子机械的p62R392L和MVNP的共表达。 3。确定MVNP与NFATD的协同作用是由于NFATD激活或NFATD的辅因子的调节所致。对负责MVNP和p62p392l对上述OCL形成的影响的分子机制的研究将提供对PD发病机理的重要见解，并与细胞和体内研究直接相关。